The insidious and sometimes precipitous development of septic shock in man involves mechanisms not clearly understood. The animal model, utilizing endotoxin or live E. coli has been extensively studied in recent years and myocardial dysfunction has been clearly documented in dogs, cats, and nonhuman primates. Septic shock in man frequently involves irreversible cardiac failure and death in spite of aggressive management and control of the infecting process. The purpose of this proposal is to identify the mechanisms of cardiac dysfunction which we have previously shown to result from the separate effects of: (a) coronary hypoperfusion and (b) endotoxin. Causes for the reported accelerated deterioration of the heart when these insults are combined will be determined. On the basis of our earlier work it is hypothesized that tissue fluid accumulation in the heart subjected to endotoxin is associated with impaired relaxation and diastolic filling properties of the left ventricle. Experiments will be conducted on isolated working left ventricles and in situ instrumented canine hearts. A chief purpose of the proposed work is to characterize the responses of hearts to the separate and combined effects of decreased coronary perfusion and endotoxin and to identify the resultant pathophysiological mechanisms responsible for myocardial dysfunction. A specific aim will be to measure the development and degree of edema formation in the heart when it is subjected to the separate and combined effects of coronary hypoperfusion and endotoxin. A chief objective is to identify causal relationships between myocardial edema and impaired left ventricular relaxation and diastolic filling resulting from coronary hypoperfusion and endotoxin. Effects of live E. coli organism-induced shock on the myocardium will be determined and compared to changes induced by endotoxin.